hiv neuropathy Learning Objectives Introduction DSPN Pathophysiology Symptoms and Signs Diagnosis

1. HIV Neuropathy and Myelopathy Sam Nightingale Sam Nightingale is a neurology registrar and MRC clinical research fellow. He is currently working with the Liverpool HIV Pharmacology Group and the Liverpool Brain Infections Group on studies of the CNS penetration of antiretroviral drugs for HIV. Edited by Prof Tom Solomon, Dr Agam Jung and Dr Sam Nightingale • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions This session provides an overview of the peripheral nervous system effects of HIV infection and antiretroviral therapy.

2. Learning Objectives • By the end of this session you will be able to: • State the causes of peripheral nerve damage in HIV • List the medications used in HIV that commonly cause peripheral nerve damage • Summarise the clinical features of nerve damage associated with the following: antiretroviral treatment, chronic HIV infection and HIV seroconversion • Describe an appropriate strategy for diagnosing and investigating an HIV positive individual presenting with painful numb feet • List the treatment and symptomatic management options for HIV-associated peripheral sensory neuropathy • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

3. Introduction • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions • Although there has been a decline in opportunistic infections related to HIV, the prevalence of peripheral neuropathy has increased due to improved longevity and the use of neurotoxic medications. • Symptomatic peripheral neuropathy occurs in 30-50% of those in the late stages of HIV, however pathological changes in the nerves can be demonstrated in nearly all. • Although most common in advanced disease, neuropathy can occur at any stage. It may be related to: • The HIV virus itself • Neurotoxic medications • Nutritional deficiencies • Alcohol excess • Autoimmune demyelination • Opportunistic infections such as CMV, hepatitis C or syphilis

4. Distal Sensory Periperal Neuropathy/DSPN • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions The most common peripheral nerve disorder encountered due to HIV is a distal sensory peripheral neuropathy (DSPN), sometimes called distal symmetrical sensory polyneuropathy (DSSP) or distal painful sensorimotor neuropathy (DPSN). DSPN usually becomes symptomatic in the later stages of infection when the CD4 count is below 200 cells/ml. However, it is not an AIDS defining illness in itself. • The risk of developing DSPN is higher if there are other neuropathic risk factors, such as diabetes, excess alcohol intake, nutritional/vitamin deficiencies and genetic neuropathies.

5. Pathophysiology • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions Neurones are damaged by direct HIV infection, as well as by locally infiltrating activated macrophages that secrete neurotoxic cytokines or other toxic metabolites. . • This process causes axonal degeneration with some demyelination. Histologically there is prominent perivascular infiltration by T-cells and macrophages and mild loss of dorsal root ganglion neurons, some of which are directly infected with HIV as demonstrated by in situ PCR.

6. Symptoms and Signs The typical presentation is painful numb feet in an individual in the late stages of HIV infection or AIDS. Significant weakness is unusual and the upper limbs are rarely involved. Symptoms progress slowly over the course of months to years. Although pain is not universal, 30-50% complain of burning or stabbing pain. This can be quite disabling and sometimes even makes walking difficult. Small sympathetic and parasympathetic nerve fibres can also be affected, causing dizziness due to postural hypotension, impaired bladder and bowel control and erectile dysfunction. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions The neurological signs are characteristic of a small fibre neuropathy. Decreased vibration sense at the toe or ankle, decreased sensitivity to pain and temperature in a stocking distribution, and depressed or absent ankle reflexes. Proprioception is usually normal. Weakness and wasting is usually mild and atrophy of intrinsic foot muscles is rarely a prominent feature. Upper limb involvement usually only occurs when the lower limb features are advanced.

7. Diagnosis Nerve conduction studies can show mild axonal damage, but may fail to demonstrate any abnormality. Thermal thresholds, which are raised with small fibre damage, are usually abnormal. Blood glucose, vitamin B12 and folate should be checked to exclude common reversible causes of neuropathy. However, if clinical features are typical of DSPN, further investigation may not be necessary. The presence of upper limb or trunk involvement, significant lower limb weakness or decreased proprioception should prompt investigation for other disorders. Nerve biopsy may be required to exclude vasculitis, demyelination or lymphomatous infiltration. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions Abnormalities rarely effect the upper limbs unless disease is very advanced

8. Medication related toxic neuropathy I • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions A dose dependent peripheral neuropathy occurs in about 10-30 % of patients treated with didanosine (ddI), zalcitabine (ddC) or stavudine (d4T). These nucleoside reverse transcriptase inhibitors (NRTIs) are known collectively as dideoxynucleoside agents or 'd-drugs'. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and other NRTIs are not generally associated with a peripheral neuropathy. Drug related toxic neuropathy is indistinguishable from HIV induced DSPN, both on clinical and neurophysiological grounds. The two conditions frequently co-exist. Presentation is the same as DSPN with a distal, symmetrical, predominantly lower limb, predominantly sensory, often painful, axonal neuropathy

9. Medication related toxic neuropathy II • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions After stopping the offending medication, neuropathic symptoms may worsen for 4–8 weeks (sometimes referred to as 'coasting') after which symptoms improve, although recovery can be slow and residual nerve damage is not uncommon. In some cases incomplete resolution may be due to coincident DSPN. The underlying mechanism may be mitochondrial toxicity from inhibition of DNA polymerase. The same mechanism could also account for the other side effects with this class of 'd drugs' e.g. pancreatitis, fulminant hepatic failure and lactic acidosis. Serum lactate is elevated in over 90% of patients with 'd-drug' related neuropathy. Electron microscopy showing mitochondria in pancreatic tissue.

10. Other Drug Treatments • In addition to antiretrovirals, several other drugs used in the treatment of HIV can cause neuropathy. These include: • Dapsone -used in the treatment of pneumocystisjiroveci pneumonia • Isoniazid - used in the treatment of TB, can cause B6 deficiency • Metronidazole – used in the treatment of amoebic dysentery and microsporidiosis • Vincristine – used in the treatment of Kaposi's sarcoma and non –Hodgkin's lymphoma • Thalidomide – used in the treatment of various cancers, wasting syndrome and severe mouth ulcers. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

11. Demyelination I Although many of the complications of HIV are related to immunodeficiency, there is also a general state of immune activation, which can result in autoimmunity, with T-cell activation and hypergammaglobulinemia. As such, HIV infection is an important cause of inflammatory demyelinating neuropathies such as Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

12. Demyelination II Guillain-Barré Syndrome (GBS)/Acute Inflammatory Demyelinating Polyneuropathy HIV infection should be excluded in any patient presenting with GBS as it can be clinically indistinguishable from GBS in HIV-seronegative individuals. It usually occurs at primary infection or seroconversion, but is rarely associated with immune reconstitution. The typical clinical presentation is an areflexic, symmetrical ascending weakness with relatively little sensory involvement. Cranial neuropathies and involvement of respiratory muscles can lead to respiratory or pharyngeal insufficiency. Autonomic involvement can cause cardiac arrhythmias and severe fluctuations in arterial blood pressure. These possible life-threatening complications require close monitoring. Symptoms progress over a maximum of four weeks, before spontaneous improvement. If there has been secondary axonal damage, recovery may be slow. Around 30% have varying degrees of residual disability. GBS due to HIV is associated with more frequent recurrent acute episodes and relapses than is seen in sero-negative individuals. CSF shows raised protein. In contrast to HIV-seronegative individuals, there is often a mild CSF pleocytosis, up to 50 cells/ml. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

13. Demyelination III Chronic, Inflammatory, Demyelinating Polyneuropathy (CIDP) Whereas GBS is an acute, self-limiting illness, CIDP is characterised by chronic progression over months, with periods of fluctuating weakness and sensory disturbance. As with GBS, CSF pleocytosis can help identify those with HIV infection. CIDP can occur at any stage of HIV infection. The reason for chronic persistence of the autoimmune demyelinating process is not known. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

14. Other Neuropathies I Vasculitic neuropathy A necrotizing vasculitis is a rare cause of neuropathy in HIV. It typically causes a mononeuritis multiplex, involving multiple individual nerves to different extents, rather than the length dependent neuropathy described earlier. The vasculitic process may also involve other organs such as heart, kidneys and muscle. Cryoglobulinaemia associated with hepatitis C co-infection can also also cause a vasculitic neuropathy. Diffuse Infiltrative Lymphocytosis Syndrome (DILS) An axonal neuropathy can occur in association with the DILS syndrome. This is a hyperimmune reaction against HIV characterised by a persistent CD8+ lymphocytosis and lymphocytic infiltration of various organs. The reported prevalence varies between 0.85 – 3%, and appears to be more common in Africans. Symptoms can resemble Sjögren's syndrome. Most patients present with bilateral parotid gland enlargement and features of the Sicca syndrome. Lymphadenopathy, splenomegaly, pneumonitis and renal dysfunction may occur. Therapeutic trials are lacking, although there can be a good response to antiretroviral and steroid therapy. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

15. Other Neuropathies II CMV Neuropathy CMV infection can cause an asymmetric axonal polyneuropathy in the late stages of HIV infection, usually at CD4 counts less than 100cells/ul and often with involvement of other organs. CMV encephalitis can also occur. CMV can be detected by PCR in the plasma and is present in the CSF in 90%. Treatment is with ganciclovir or foscarnet therapy. Relapse is common unless immune function can be improved. The image below shows a gross micrograph of a coronal slice of brain from a patient with HIV disease who has CMV ventriculitis (ependymitis). It shows dilated lateral ventricles adjacent to the basal ganglia. The lining of the ventricles (the ependyma) is reddened and inflamed. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

16. Other Neuropathies III Neuropathy Due to Other Diseases Syphilis should always be excluded by serology and there should be a low threshold for treatment. Tuberculosis or lymphoma affecting nerve roots, caudaequina or meninges can cause an acute or subacutepolyradiculopathy with flaccid paraparesis of the lower limbs, bowel dysfunction and a sensory level. Other important causes of a neuropathy are alcohol abuse, diabetes mellitus and malnutrition, particularly in patients with malignancy, gastrointestinal diseases or wasting syndromes. The images below show cutaneous secondary syphilis. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

17. Treatment Discontinue neurotoxic drugs if possible. HIV should be treated with a fully suppressive regime and superimposed infections such as CMV treated appropriately. Intravenous immunoglobin and plasmapheresis may be required in GBS and CIDP depending on the severity. Poor nutrition needs addressing and if in doubt, vitamin supplements should be given. Alcohol should be avoided and high blood sugars controlled. Individuals with peripheral sensory neuropathy should receive advice on foot care to avoid painless injury to numb toes or feet. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

18. Treatment II • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions Pain Relief Pain can be a big problem in HIV infection. 80% of HIV infected individuals with pain receive inadequate analgesia compared with 40% with cancer. This may be due to stoicism and reluctance to report symptoms or the stigma of substance abuse. Neuropathic pain can be managed with anticonvulsants, antidepressants, analgesics and topical treatments, however neuropathic pain is notoriously refractory to treatment. Gabapentin tends to be first line and Lamotrigine has been shown to be effective in HIV neuropathy. Pregabalin and Amitriptyline are used because of their effectiveness in diabetic neuropathy, although a small trial of Amitriptyline in HIV neuropathy failed to show benefit. Topical analgesics Capsaicin and Lignocaine patch have demonstrated efficacy.

19. HIV associated Myelopathy I • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions HIV myelopathy is most common in those with advanced immunosuppression and often coincides with neurocognitive symptoms. Before antiretroviral therapy, HIV myelopathy was seen in up to 20% but is now much less common. In contrast to HIV encephalopathy, astrocytes and neurons do not appear to be directly infected and the exact mechanism of damage is not clear. Post-mortem histology shows vacuoles with lipid-laden macrophages in the spinal cord, so HIV myelopathy is often referred to as 'vacuolar myelopathy'. Although such features are common at autopsy, much fewer have clinically evident myelopathy during life.

20. HIV associated Myelopathy II Myelopathy typically presents in the legs with a slowly progressive symmetrical weakness, stiffness and sensory loss and sphincter dysfunction. There may be signs of spasticity with increased tone, hyper-reflexia and extensor plantar responses. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions • Limbs may be numb or dysaesthetic, but as the damage is diffuse in HIV myelopathy, a discrete sensory level is unusual and suggests a different cause. • Imaging with MRI is often normal, or may show non-specific features such as spinal cord atrophy or diffuse non-enhancing high signal area

21. HIV associated Myelopathy III • CSF examination is usually normal, or has non-specific abnormalities, such as a raised white cell count (up to 50 cells/μl). • HIV myelopathy is a diagnosis of exclusion. • Imaging and lumbar puncture are important to rule out other causes of myelopathy, such as:. • Spinal cord compression • Sub-acute combined degeneration of the cord due to B12 deficiency • Infections with cytomegalovirus, varicella-zoster virus, herpes simplex virus and HTLV-1 • There is no specific treatment. Antiretroviral therapy may initially lead to significant improvement and may slow the usual disabling progression. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

22. Key Points • Neuropathy in HIV is common and has a number of different causes. • Most commonly neuropathy is due to HIV itself, or one of a number of neurotoxic medications used in HIV. These causes are clinically indistinguishable and frequently overlap. • HIV infection can be associated with a Gullian-Barre Syndrome, particularly at seroconversion. HIV testing should be considered in all presenting with GBS. • Specific treatment should be aimed at the underlying cause. HIV neuropathy is frequently painful and there are a number of symptomatic treatments. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

23. Summary • Having completed this session you will now be able to: • State the causes of peripheral nerve damage in HIV • List the medications used in HIV that commonly cause peripheral nerve damage • Summarise the clinical features of nerve damage associated with the following: antiretroviral treatment, chronic HIV infection and HIV seroconversion • Describe an appropriate strategy for diagnosing and investigating a HIV positive individual presenting with painful numb feet • List the treatment and symptomatic management options for HIV-associated peripheral sensory neuropathy • References and Further Reading • Attala N et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. European Journal of Neurology 2010;17: 1113–1123. • Simpson DM et al. Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology. 2010;74(5):413-20. • Simpson DM et al. HIV neuropathy natural history cohort study: assessment measures and risk factors. Neurology. 2006;66(11):1679-87. • Verma A. Epidemiology and clinical features of HIV-1 associated neuropathies. J PeripherNerv Syst. 2001;6(1):8-13. • Simpson DM. Selected peripheral neuropathies associated with humanimmunodeficiency virus infection and antiretroviral therapy. J Neurovirol. 2002;8 Suppl 2:33-41. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions

24. Question 1 Select the single best answer from the options given. Click on the answer to see if it is correct and read an explanation. • hiv neuropathy • Learning Objectives • Introduction • DSPN • Pathophysiology • Symptoms and Signs • Diagnosis • Medication related toxic neuropathy • Demyelination • Other Neuropathies • Treatment • HIV Myelopathy • Key Points • Summary • Questions A 37-year-old lady complains of numb feet. She has a constant burning sensation and they are painful to touch. She has been on ART for 12 years and currently takes Atripla (efavirenz/emtricitabine/tenofovir). Despite treatment her CD4 is 120 cells/ul. She is overweight and has recently been diagnosed with type 2 diabetes. Select one answer from the list below. a.Distal sensory peripheral neuropathy (DSPN)b. Medication related toxic neuropathyc. Demyelinationd. Nutritional deficiencye. Other cause of neuropathy A 37-year-old lady complains of numb feet. She has a constant burning sensation and they are painful to touch. She has been on ART for 12 years and currently takes Atripla (efavirenz/emtricitabine/tenofovir). Despite treatment her CD4 is 120 cells/ul. She is overweight and has recently been diagnosed with type 2 diabetes. Select one answer from the list below. a.Distal sensory peripheral neuropathy (DSPN)b. Medication related toxic neuropathyc. Demyelinationd. Nutritional deficiencye. Other cause of neuropathy